Intranasal epinephrine: Does it stack up to the intramuscular standard?

Anaphylaxis remains a life-threatening emergency, with epinephrine being the cornerstone of treatment. Despite its vital role, adherence to carrying and using epinephrine autoinjectors is suboptimal. Patients often cite needle phobia, inconvenience, and fear of improper administration as reasons for not carrying their prescribed devices, a persistent problem that our previous coverage has explored. This leads to delayed or missed doses, increasing the risk of severe outcomes. A non-injectable, rapidly absorbed formulation could significantly improve patient compliance and, by extension, clinical outcomes.¹

Oppenheimer and colleagues designed a randomized, open-label, two-period crossover study to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of neffy compared with intramuscular epinephrine. The trial enrolled 36 healthy adults with a history of seasonal allergic rhinitis. Investigators induced allergic rhinitis with nasal obstruction using a validated environmental exposure chamber, creating a real-world challenge for intranasal drug delivery. Participants received either a single dose of neffy (2 mg) or IM epinephrine (0.3 mg) in a crossover design, with a washout period between treatments. The primary PK endpoints included maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) at various intervals.¹

The Pharmacokinetic Profile in Induced Rhinitis

The study found that neffy achieved systemic epinephrine exposure comparable to IM epinephrine, even under conditions of induced allergic rhinitis. The geometric mean ratio for AUC_0-30min (neffy/IM) was 0.84 (90% CI, 0.76-0.93), falling within the predefined equivalence range of 0.80-1.25. This early exposure is critical for anaphylaxis treatment, where rapid onset of action is paramount. C_max for neffy was 1008 pg/mL (90% CI, 896-1133 pg/mL) compared to 1200 pg/mL (90% CI, 1067-1350 pg/mL) for IM epinephrine, with a geometric mean ratio of 0.84 (90% CI, 0.73-0.97). While C_max was slightly lower for neffy, the rapid absorption kinetics suggest clinical relevance.¹

Peak plasma concentrations (T_max) were also similar, with a median T_max of 15 minutes for neffy and 10 minutes for IM epinephrine. This difference of 5 minutes is unlikely to be clinically meaningful in the acute management of anaphylaxis, where the goal is to achieve therapeutic levels quickly. The study also evaluated repeat dosing, administering a second dose 10 minutes after the first. This simulated a scenario where a patient might require additional epinephrine due to persistent or worsening symptoms. The PK profile remained consistent with the first dose, indicating reliable absorption even with repeated intranasal administration.¹

The investigators also assessed pharmacodynamic markers, including changes in blood pressure and heart rate. Both neffy and IM epinephrine produced similar increases in systolic blood pressure (SBP) and heart rate (HR), reflecting comparable systemic adrenergic effects. The mean maximum increase in SBP was 21.2 mmHg for neffy and 24.7 mmHg for IM epinephrine. For heart rate, the mean maximum increase was 16.2 bpm for neffy and 18.9 bpm for IM epinephrine. These PD responses confirm that the intranasal formulation delivers a biologically active dose of epinephrine, triggering the expected physiological responses necessary to counteract anaphylaxis.¹

Safety and Tolerability

neffy was generally well-tolerated in the study population. The most common adverse events (AEs) associated with neffy were mild and transient, primarily related to nasal irritation. These included nasal discomfort, sneezing, and rhinorrhea. No serious adverse events were reported with either treatment. The safety profile is an important consideration for a product intended for self-administration, as a favorable tolerability profile can enhance patient acceptance and adherence. The local nasal effects were consistent with other intranasal medications and did not appear to significantly impede absorption.¹

The study specifically addressed the concern that allergic rhinitis with nasal obstruction might impair intranasal drug absorption. By inducing allergic rhinitis in participants, the researchers created a challenging environment for nasal drug delivery. The consistent PK and PD results under these conditions suggest that neffy's absorption is robust enough to be effective even when patients experience nasal congestion, a common symptom during allergic reactions. This is a vital point, as many patients experiencing anaphylaxis may also have underlying allergic rhinitis or develop nasal symptoms as part of their allergic reaction.¹

The Mechanism of Intranasal Delivery

Intranasal drug delivery bypasses first-pass metabolism, allowing for rapid absorption directly into the systemic circulation through the highly vascularized nasal mucosa. This route offers a non-invasive alternative to injections, which can be particularly advantageous in emergency situations or for individuals with needle phobia. The formulation of neffy is designed to optimize absorption, ensuring that epinephrine can quickly reach therapeutic concentrations. The nasal cavity provides a large surface area for absorption, and the rich blood supply facilitates rapid drug uptake.¹

The challenge with intranasal delivery, particularly for a drug like epinephrine that requires precise dosing and rapid onset, lies in ensuring consistent absorption. Factors such as nasal congestion, mucociliary clearance, and individual anatomical variations can influence drug uptake. The study's design, which included induced allergic rhinitis, aimed to simulate a worst-case scenario for absorption, providing stronger evidence for the drug's reliability. The positive results suggest that the formulation effectively overcomes these potential barriers.¹

Comparing Intranasal to Intramuscular

Intramuscular epinephrine has been the standard of care for anaphylaxis for decades due to its rapid and reliable absorption. But its administration requires a needle, which can be a significant barrier for many. Patients may hesitate to use an autoinjector, or caregivers may be reluctant to administer it, leading to delays that can be life-threatening. The challenges of precise dosing and administration are well-documented across various drug classes. neffy offers a needle-free alternative that could address these issues, potentially increasing the likelihood of timely administration.¹

The comparable PK and PD profiles observed in this study are important for patient safety and efficacy. While C_max was slightly lower with neffy, the rapid achievement of therapeutic concentrations and similar AUC_0-30min values indicate that the intranasal route can provide sufficient systemic exposure to manage an acute anaphylactic reaction. The early time points for AUC are particularly important, as they reflect the amount of drug available in the bloodstream during the critical initial phase of anaphylaxis. The data suggest that neffy could offer a similar therapeutic window to IM epinephrine, but with the added benefit of a less intimidating administration method.¹

Where it Falls Short

The study was conducted in healthy adults with induced allergic rhinitis, not in patients actively experiencing anaphylaxis. While induced rhinitis provides a relevant challenge for nasal absorption, the physiological state of a patient in full-blown anaphylaxis, with potential hypoperfusion or altered nasal blood flow, might differ. The generalizability of these findings to the full spectrum of anaphylactic reactions, particularly the most severe cases, requires further investigation in real-world settings. The relatively small sample size of 36 participants also means that rare adverse events or subtle PK differences might not have been detected.¹

But the open-label design is an obvious caveat. While PK/PD studies are often open-label due to the nature of drug administration and measurement, it introduces potential for bias in subjective assessments, though objective PK/PD markers mitigate this to some extent. The study also focused on a single dose of neffy (2 mg) and IM epinephrine (0.3 mg). While repeat dosing was explored, the optimal dosing strategy for neffy in various anaphylaxis scenarios, particularly in pediatric populations or those with specific comorbidities, still needs to be fully elucidated.¹

The trial was not powered to detect differences in clinical outcomes, such as resolution of anaphylaxis symptoms or prevention of biphasic reactions. Its primary objective was to establish pharmacokinetic and pharmacodynamic equivalence. Future studies would need to evaluate neffy in a clinical trial setting with actual anaphylaxis patients to confirm its efficacy in preventing severe outcomes. Still, the robust PK/PD data provide a strong foundation for its potential clinical utility.¹